Sutureless Aortic Valve Replacement vs. Transcatheter Aortic Valve Implantation in Patients with Small Aortic Annulus: Clinical and Hemodynamic Outcomes from a Multi-Institutional Study

Objective This study aimed to compare hemodynamic performances and clinical outcomes of patients with small aortic annulus (SAA) who underwent aortic valve replacement by means of sutureless aortic valve replacement (SUAVR) or transcatheter aortic valve implantation (TAVI). Methods From 2015 to 2020, 622 consecutive patients with SAA underwent either SUAVR or TAVI. Through a 1:1 propensity score matching analysis, two homogeneous groups of 146 patients were formed. Primary endpoint: all cause-death at 36 months. Secondary endpoints: incidence of moderate to severe patient-prosthesis mismatch (PPM) and incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) Results All-cause death at three years was higher in the TAVI group (SUAVR 12.2% vs. TAVI 21.0%, P=0.058). Perioperatively, comparable hemodynamic performances were recorded in terms of indexed effective orifice area (SUAVR 1.12 ± 0.23 cm2/m2 vs. TAVI 1.17 ± 0.28 cm2/m2, P=0.265), mean transvalvular gradients (SUAVR 12.9 ± 5.3 mmHg vs. TAVI 12.2 ± 6.2 mmHg, P=0.332), and moderate-to-severe PPM (SUAVR 4.1% vs. TAVI 8.9%, P=0.096). TAVI group showed a higher cumulative incidence of MACCEs at 36 months (SUAVR 18.1% vs. TAVI 32.6%, P<0.001). Pacemaker implantation (PMI) and perivalvular leak ≥ 2 were significantly higher in TAVI group and identified as independent predictors of mortality (PMI: hazard ratio [HR] 3.05, 95% confidence interval [CI] 1.34-6.94, P=0.008; PPM: HR 2.72, 95% CI 1.25-5.94, P=0.012). Conclusion In patients with SAA, SUAVR and TAVI showed comparable hemodynamic performances. Moreover, all-cause death and incidence of MACCEs at follow-up were significantly higher in TAVI group.


INTRODUCTION
Small aortic annulus (SAA) is an anatomic feature that represents an important concern in patients undergoing aortic valve replacement (AVR) [1] .Small sizes (≤ 23 mm) of stented aortic bioprostheses have an effective orifice area (EOA) smaller than the native aortic valve area, which may lead to patient-prosthesis mismatch (PPM) [1,2] .As a matter of fact, PPM occurs when the EOA of a normally functioning prosthetic valve is too small in relation to the patient's body surface [2] .The presence of moderate (< 0.85 cm 2 /m 2 and > 0.65 cm 2 ) or severe (< 0.65 cm 2 /m 2 ) PPM has been demonstrated to produce detrimental effects on patients' outcomes, jeopardizing left ventricular reverse remodeling, hypertrophy regression, and functional recovery [1,3] .Surgical aortic annulus enlargement was demonstrated to be a viable surgical strategy to reduce PPM rate, allowing surgeons to implant larger bioprostheses.However, aortic annulus enlargement increases surgical complexity and risks and is rarely performed [4] .Nevertheless, the use of stentless bioprostheses (SB) reduced the risk of PPM in patients with SAA since the absence of a rigid stent allows the use of larger prostheses.However, the major drawback of SB is the increased ischemic and cardiopulmonary bypass (CPB) times for implant, despite no differences in terms of intensive care unit (ICU) and hospital length of stay were demonstrated [5,6] .Several studies showed that transcatheter aortic valve implantation (TAVI) offered better hemodynamic results with a reduced incidence of PPM especially in patients with a SAA [7,8] .In this specific subset of population, self-expandable valves (SEV) showed better hemodynamic performances when compared to balloonexpandable valves (BEV) [9,10] .Sutureless aortic valves proved to have larger EOAs for any given size compared to stented bioprostheses and to provide good hemodynamic performances, comparable to stentless valves.In addition, sutureless valves can be implanted with significantly shorter aortic cross-clamping and CPB times, overcoming the drawback of SB [11] .Patients receiving sutureless valves had shorter invasive ventilation time and ICU and hospital stay as well as the need for red blood cell transfusions when compared to stented valves [11] .The aim of this study was to compare hemodynamic performances and outcomes of sutureless aortic valve replacement (SUAVR) vs. TAVI in elderly patients affected by aortic stenosis (AS) with a small aorta undergoing surgical AVR employing balloon-expandable or self-expandable bioprostheses.(iEOA) (moderate PPM iEOA < 0.85 cm 2 /m 2 ; severe PPM iEOA < 0.65 cm 2 /m 2 ) [1] .Transesophageal echocardiography was performed to assess intraoperative implant success according to Valve Academic Research Consortium (VARC) III criteria [12] .Prosthetic aortic valve regurgitation was defined moderate to severe according to VARC III criteria (vena contracta > 4 mm, pressure half-time 200-500 ms, regurgitant volume > 30 ml/beat) [12] .As far as TAVI concerns, oversizing was analyzed by the physicians involved in the individual case and did not exceed 20%.For sutureless valves, oversizing was not performed, as recommended in the Company's manual.

Statistical Analysis
The normality of continuous distributions was assessed using the Kolmogorov-Smirnov test.Normally and skewed distributed variables were presented as mean with standard deviation and median with 25 th and 75 th percentiles (interquartile range boundaries), respectively.Student's t-test or Mann-Whitney U test were used for normally distributed or skewed distributed variables, respectively.Categorical variables were expressed as frequency and percentage and were compared using the Chi-square test.
Preoperative covariates were adjusted with 1:1 nearest-neighbour propensity score matching without replacement (caliper 0.06), obtaining two balanced groups (matched [Table 1] and unmatched [Table E1]).Balance check was performed analyzing the standard mean difference between the two groups.A visual inspection of the standard mean difference with the Love plot was also performed.The matched standardized differences of each covariate in the matched population were < 10% (Figure 1).The Kaplan-Meier method was used to assess overall survival and freedom from MACCE.Group difference analysis was evaluated using the log-rank test

Operative Results
In the SUAVR group, a minimally invasive strategy was adopted in 60 ) patients had a size S Acurate TA™ self-expandable bioprosthesis.Moreover, in 71.9% of patients, TAVI procedure was carried out through transfemoral (TF) approach, while transapical (TA) approach was adopted in 26.0% of cases, and subclavian, transaortic, and transcarotid approaches in 2.0% of the remaining cases.
A second valve implantation was required for technical failure in three (2.0%) patients in the TAVI group (two patients undergoing Edwards SAPIEN® and one patient receiving an Evolut™ R valve).
Emergency conversion to open surgery was required during three (2.0%) procedures: left coronary ostium obstruction and for aortic annular rupture occurred in one (0.7%) and two (1.4%) patients, respectively.In the SUAVR group, one patient was converted to stented valve implantation due to intraoperative annular rupture, while one patient required a second cross-clamp for valve repositioning (Table E2).
Thirty-day all-cause mortality was higher in the TAVI group (matched: SUAVR 1.4% vs. TAVI 6.2%, P<0.032).Of note, as a subgroup analysis, TA group showed a higher mortality rate compared to TF approach (TA: 13.2% vs. TF:

DISCUSSION
To our knowledge, this is the first multi-institutional study comparing the hemodynamic performances of sutureless aortic valves vs. TAVI in patients with a SAA.Although not being randomized, this retrospective analysis was designed as propensity matched comparison to reduce confounding factors.
The major findings of this study were: 1) SUAVR and TAVI showed up to one year comparable hemodynamic performances in terms of iEOA, transvalvular gradients, and incidence of moderate to severe PPM; 2) at three years, patients treated with TAVI showed a significant reduction of iEOA with a significant higher rate of moderate to severe PPM when compared to SUAVR; 3) at one and three years, TAVI group showed a higher all-cause mortality when compared to SUAVR, significantly in the unmatched population; 4) at one and three years, TAVI group showed a significantly higher rate of MACCEs in the matched and unmatched groups; 5) multivariable Cox regression analysis showed PPM and PMI as independent predictors of mortality (matched PPM: HR 2.72, 95% CI 1.25-5.94,P=0.012) (matched: PMI: HR 5.2, 95% CI 2.0-14.3,P=0.012).
The current study analyzed the influence of treatment strategy in patients with AS and SAA for which the risk of suboptimal valve hemodynamics and PPM is relevant.PPM is a well-known condition which may occur in patients with SAA both after surgical AVR and TAVI procedures.Small size of stented bioprostheses (≤ 21 mm) in surgical AVR likely leads to PPM in patients with body surface area (BSA) > 1.7 [1,13] .The risk of PPM Brazilian Journal of Cardiovascular Surgery   VARC=Valve Academic Research Consortium may be reduced by using annulus enlargement techniques, allowing the use of larger bioprostheses [14] .However, annulus enlargement is seldom performed [7] , as reported by Pibarot et al., which found in the Placement of AoRTic TraNscathetER Valves (PARTNER) cohort A analysis, that patients undergoing surgical AVR had a significantly higher incidence of moderate and severe PPM when compared to TAVI.In addition, in patients with a SAA treated with stented bioprosthesis, severe PPM were found in more than one-third of cases (34%), clearly indicating a suboptimal surgical treatment [7] .
However, the issue of PPM remains relevant even in patients undergoing transcatheter valve implantation, since Pibarot et al., in the PARTNER trial Cohort-A analysis, reported in the subset TAVI group with SAA an incidence of moderate and severe PPM of 27% and 20%, respectively [7] .Herrmann et al. [15] , analyzing data on more than 60,000 patients undergoing TAVI from the STS/ACC TVT Registry™, reported an incidence of moderate and severe PPM of 25% and 12%, respectively.These authors showed that PPM was associated with a  [15] .Data from TAVI Registries (International Multicenter Registry to Evaluate the Performance of Self-Expandable Valves in Small Aortic Annuli [TAVI-SMALL], Optimized transCathEter vAlvular interventioN-Transcatheter Aortic Valve Implantation [OCEAN-TAVI]), reporting outcomes in SAA patients, are consistent with the results of the abovementioned study [8,16] .
Results of the present study confirm these findings and confirm the progressive decrease of the iEOA over time in the TAVI group, with a constant increase of moderate to severe PPM incidence [16] .
Progressive reduction of the iEOA may be due to an early degeneration process of TAVI caused by leaflet stress, and/or to a progressive degeneration and calcification of the "left-in-place" native valve [17] .Moderate and severe structural valve deterioration at mid-term in TAVIs have been reported up to 10.8% and 12.9%, respectively [18] .Sutureless aortic valves were designed to overcome the major hemodynamic drawbacks of stented bioprostheses.The absence of an outer stent provides a greater EOA with a significant lower incidence of PPM when compared to stented valves [18][19][20] .On this Brazilian Journal of Cardiovascular Surgery regard, Tasca et al. demonstrated in small valve sizes (sutureless small and medium) an in-vitro hemodynamic performance as those of native aortic valves.These data are consistent with the outcomes reported by Shalabi and Rubino [18,21] that showed in patients with SAA a postoperative mean iEOA of 1.12 cm 2 /m 2 at rest [19] , with an increment of 30% of iEOA during stress echocardiography [21] .However, some technical pitfalls, such as sutureless oversizing and an incomplete annular decalcification, may jeopardize SUAVR hemodynamics, increasing the risk of valve dysfunction and PPM as reported by Belluschi and Glauber [20,22] .One of the main findings of the current study is a stable and reliable hemodynamic performance of SUAVR without a significant iEOA reduction over time, avoiding the late development of PPM.Meuris et al. analyzing a large series of sutureless AVR demonstrated a survival freedom from structural valve degeneration of 97% at 10 years [23] .
Of note, in this study, the presence of moderate to severe PPM increased 2.5-fold the risk of mortality at follow-up.Similarly, Pibarot et al. reported in 2006 a two-fold and an 11-fold incremented risk of mortality for patients with moderate and severe PPM, respectively [1] .
An additional important finding of the present study is the incidence of moderate to severe PVL significantly higher in the TAVI cohort when compared to the SUAVR group (6.8% vs. 1.4%, respectively), which is consistent with previous studies [3,8,9] and TAVI registries (OCEAN-TAVI, PARTNER II) [9,24] , showing that moderate to severe PVL increases over the years, particularly in BEV.This is associated with a significant decrease in survival at two years [24] .This study showed significantly higher rates of mortality in the TAVI group (6.1%) when compared to the SUAVR group (1.4%) at 30 days.The early mortality rate of the TAVI group could be explained by the higher percentage of patients undergoing TA procedures in this study (26.0%), higher than those in PARTNER II and Surgical Replacement and Transcatheter Aortic Valve Implantation (or SURTAVI) (17.2% and 0%, respectively).However, mortality of the TAVI group at one year and three years was significantly higher than SUAVR only in the unmatched group (Figure 3).These outcomes on TAVI patients are consistent with results reported in the OCEAN-TAVI registry and TAVI-SMALL at 12 and 36 months [9] .It should be remembered that these patients had a lower BSA than the average population (< 1.60 m 2 in the matched group), meaning, besides a smaller aortic annulus, smaller vascular accesses [25] .Consequently, transvessel approaches were either not always viable or carried an elevated risk of vascular complications, making the TA approach the most feasible option.A relevant finding of the current study is the incidence of AV blocks and left bundle branch block requiring permanent PMI that was significantly higher in the TAVI group than in the SUAVR group (11.5% vs. 4.5%, respectively).Those results are consistent with data from the OCEAN-TAVI and TAVI-SMALL registries (13.3% and 15.6%, respectively), while data concerning SUAVR are comparable to those reported in literature [18] .The lower incidence of PMI in SUAVR, which basically has the same expandable self-anchoring stent of TAVI, may be explained by the removal in SUAVR of the native aortic valves and annular calcification, which may reduce the compression causing injury to the conduction tissue [22] .At multivariable Cox regression analysis of the overall study population, the PMI implantation was an important predictor of mortality with a three-fold increased risk of death at three years (HR: 3.05, 95% CI 1.34-6.94).

Limitations
The major limitation of the current study is the lack of randomization.This could be only partially corrected by propensity score matching, which reduced the heterogeneity between groups, but could not eliminate enrollment biases.However, enrollment biases may be also present in randomized comparisons when selection at the entry point of the studies takes only a small percentage of patients having the inclusion criteria.

CONCLUSION
In conclusion, this study showed that postoperative hemodynamic performances of TAVI vs. SUAVR are comparable up to one year postoperatively.However, TAVI patients showed a decline in hemodynamic performance and an increase in PPM at three years, suggesting early device degeneration.TAVI patients are burdened over time by an increased incidence of moderate to severe PVL and by higher rates of permanent PMI.PPM and PMI were associated with a significant reduction in survival both in SUAVR and TAVI groups.
In patients with AS and SAA, sutureless bioprostheses significantly improved hemodynamics and MACCEs at three years when compared to TAVI.

No financial support.
No conflict of interest.

Table 1 .
Patients' preoperative characteristics.Postoperative results are listed in Table2for the matched and in TableE3for the unmatched groups.

Table E1 .
Preoperative patients' characteristics in unmatched groups.

Table E3 .
Postoperative outcomes in unmatched groups.